The overall goal of this project is to identify patterns of brain function that contribute to or result from dependence on drugs, and to suggest leads in the development of new treatment methods. Our research strategy is use positron emission tomography (PET) to evaluate the effect of various drugs of abuse and cognitive activation on cerebral metabolic rates for glucose metabolism using [F-18]fluorodeoxyglucose as the radiotracer and cerebral blood flow using [O-15]-water as the radiotracer. Both of these methodologies provide indices of human brain function . The research includes assessments of cognitive and neuropsychological performance during the imaging sessions. The relationship between cocaine craving and cerebral glucose metabolism in cocaine abusers was examined. Cocaine cues elicited a higher degree of craving than previously reported and resulted in left hemispheric activation of lateral amygdala, lateral orbitofrontal cortex and rhinal cortex, and right hemispheric activation of dorsolateral prefrontal cortex and cerebellum. The intensity of activation in these areas (except cerebellum), as well as left insula, was also correlated with craving. Deactivation occurred in left ventral pole and left medial prefrontal cortex. The results suggest that induction of drug craving involves a neural network that assigns incentive motivational value to environmental stimuli through the co-activation of brain regions that process information about memories and emotions. The effect of nicotine on cerebral blood flow and memory in smokers and ex-smokers were examined. Abstinent smokers, but not ex-smokers showed significantly improved performance on the memory test after given nicotine gum, compared with their performance after placebo gum. The decreased blood flow in some regions of the smokers' brains compared with increased cerebral blood flow in ex-smokers after chewing nicotine gum is the first evidence of tolerance to nicotine measured directly in the human brain. The effects of the benzodiazepine, triazolam (Halcion), on memory performance and cerebral blood flow revealed an association between decreased blood flow in the anterior cingulated cortex, the cerebellum and precuneous and impaired performance on the memory task compared to the placebo condition. Studies of individuals with histories of cocaine abuse demonstrated differences in the effects on blood flow while cocaine abuse and their matched controls performed tasks of sustained attention (Stroop Color Word Interference task) and decision-making (Iowa gambling task). Compared to controls, cocaine abusers have lower metabolism in the anterior cingulate gyrus and in the orbitofrontal cortex, respectively during performance of these tasks. Studies in individuals with a history of opiate abuse showed that individuals that have been withdrawn from methadone maintenance therapy have lower glucose metabolism in the prefrontal, temporal and anterior cingulated cortices than either currently methadone maintained individuals or those who have had no history of drug abuse. These results suggest that administration of methadone appears to normalize metabolic deficits in individuals with a history of opiate abuse. A new initiative is investigating the effects of an 'emotion-laden' task on cerebral blood flow and electrophysiological responses in polydrug abusing volunteers.